The Half Decent Pharmaceutical Chemistry Blog

As usual, Monday is a day for news and funny stuff. Today is no exception: this is a joyful day, because I've brilliantly done a neuroscience exam, this morning.

This means I'll be at pub for the next 12 hours, of course.

Now, before leaving for my deserved...refreshment, let me tell you that yesterday I forgot to say that, next Sunday, the 24th, there won't be any Sunday's Family Reunion, since here, where I live, the day before Christmas is somehow more important than Christmas itself. These mad Italians...
The series will be back on December 31 with a special New Year's Eve edition.

Oh, and happy birthday, movies! I'll toast in your honour as well.

Seeya!

It is not unusual for an important man to have (many) sons and daughters, but only one who is able to follow his steps. A bright example are the Coumarins and the virtuous heir is Warfarin.

Dicumarol is a natural substance which was discovered as a rodenticides and, from observations on hemorrhages induced in cattle, anticoagulant.
Dicumarol, however, is not used any more because it's as unreliable as its derivatives (severe gastrointestinal effects), but, nevertheless, it has, in my opinion, to be regarded as a brilliant natural drug which leaded to the most used anticoagulant, Warfarin.
Clinical use of phenindione can result in many side effects in liver and kidney. Phenprocoumon is highly toxic too.

Warfarin, as sodium salt, is an orally administered drug with terrific 100% bioavailability. Not only does it prevent the carboxylation of prothrombin, but also several clotting factors are inactivated. This multiple activity is achieved thanks to the common biochemical pathway normally involved, the so-called vitamin K cycle, or, basically, the oxidation of vitamin K epoxide, blocked by this substance.



Although these drugs cause adverse effects, the most interesting feature are the huge number of interactions, pharmacokinetic and dynamic.

Adverse effects may be due to an overdose, which results in uncontrolled hemorrhages, cutaneous necrosis, infraction of breast or intestine and venous thrombosis because of a reduced activity of protein C.

Pharmacokinetic interactions with other drugs are mainly caused either by induction or inhibition of cit. P450 isoforms. Cimetidine, disulfiram, metronidazole, fluconazole, sulfamethoxazole and trimethoprim augment hypoprothrombinemia.
On the contrary, barbiturates and rifampin, inducing hepatic enzymes, partly reduce the effectiveness of coumarin anticoagulants.

The way other drugs may alter the outcome of an anticoagulant therapy, pharmacodynamically, are many and different. Aspirin dangerously increases the effects of warfarin due to its action on platelet metabolism; heparin inhibits many clotting factors as well as warfarin; interestingly, even cephalosporins, albeit solely those belonging to the third generation, do the same since they tend to kill some intestinal bacteria which generally yield vitamin K.
Inhibition might be achieved with some diuretics, such as spironolactone, but it's mainly due to genetic hereditary mutations of vitamin K cycle molecules.

Fortunately, many important drugs can be taken (relatively!) light-heartedly: benzodiazepines and opioids (both future protagonists in the Psycho Week), indomethacin (check out an article next week) and most antibiotics don't alter the effects of these anticoagulants.

Good evening and welcome! We have a very special guest tonight: Ephedrine. I should say a Chinese guest, actually, since this drug has been used there for 2,000 years!
We had to wait until the 1920s, when it was launched on the Western markets as the very first sympathomimetic drug ever.

Interestingly, although a phenylisopropylamine and not a proper cathecolamine, ephedrine shows the same effectiveness of terrificly potent sympathomimetics. This drug has incredibly high bioavailability, its effect lasts many hours, it's a reliable decongestant, has a use in asthma and, but is generally considered an adverse effect, central stimulant. How it acts? It increases the release of norepinephrine.

Now, let's see how to synthesize it.



Well, it's certainly not the most advanced synthesis, but, none the less, I chose it because I find amazing these easy preps of natural drugs, in particular when they are so popular.

This one, besides, has some party pieces and it's likely to be the more useful I've discussed here, so far.

Although we begin with a banal Friedel-Craft acylation, the following step is just brilliant: a rather simple mechanism explains how our mighty phenyl ketone reacts with an alkyl nitrite.
However, you can't use ANY alkyl nitrite, but, apparently, R should present six carbons.

The oxime becomes a diketone thanks to mild acidic conditions. But this diketone is a definitely a cool molecule. The two carbonyls have slightly different reactivity: the later yielded is more likely to react, because it is more aliphatic.
Thus, it will be the only one reduced by the final reductive amination.

Although four years ago I was still at high school, since university began, there has been a bit of tradition going on among us, former classmates: the annual pre-Christmas reunion.

Every year, the week before December 25 (so, the next one), we meet in some place to have dinner together and talk about what we have been doing that year.

 

 

Two hours ago, I was texted by a friend who told where and when we are going to have this meeting.
That made me remember of last year's dinner, when one of the lads, not a particular friend of mine, annoyed me with his boring questions about beta-blockers all the time.

Let me explain: he is a pretty successful violinist, who, with a surprisingly smart decision, decided to not go to university and went on playing his instrument. That's fair.
He plays in important orchestras all over the world with his mates, wh are, apparently, anxious, insecure, middle-aged people.

He asked me about beta-blockers for a variety of reasons: he can't use internet (he likes to act like a middle-aged man, what a d***), he thought it was my turn to have the pleasure of a chat with him or he was just pathetically looking for human compasion, sharing a view of his life. Well, you looked in the wrong place, dear.

However, beta-blockers are widely misused by a lot of people, even scientists (chemists included). There's something which all these people has in common: very, very insecure as they are, they even have to perform in front of (relatively) huge crowds.

 

 

While in the Seventies musicians playing in front of massive crowds would have opted for cocaine or other drugs (depending on the attitude), we live in a dark age, where antihypentensive drugs rock.

Anxious performers (even a scientist who speaks at a conference) find these drugs really effective, although they fortunately use them a lower dosage than those who take them for, say, hypertension.

A healthy person won't sense any change for what concerns his/her blood pressure, but a remarkable difference is the negative inotropic and chronotropic effect: atrioventricular conduction is slowed even at low dose, for example.

Adverse effects, such as bronchoconstriciton, may appear, but likely to be very moderate and overwhelmed by the feel-good mood.

However, if I were an asthmatic and a musician, I wouldn't try them. Same story with diabetes: they are reported to be capable of impairing recovery from hypoglycemic crisis.
Not to mention, the effectiveness of, for example, a chronic use of propranolol (the most used for this non-therapeutic purpose) in terms of increasing the concentration of VLDL, with long-term consequences such as atherosclerosis.

Generally, I believe, beta-blockers calm anxious performers mainly because of their placebo effect: it's not important what I actually swallow, if I firmly believe it will help me as usual.

 

I haven't yet decided if I'll go this year.

Looking back at the previous drugs of the week, they were all rather small molecules with either interesting features and/or thrilling adverse effects.

This week, though, I have opted for a huge molecule, rifampin, with remarkable properties. Somehow, you should consider it a masterpiece.

Now, this ginormous drug is one of the derivatives of an antibiotic, rifamycin, produced by Streptomyces mediterranei. It has terrific effectiveness against cocci, some enteric bacteria and mycobacteria. In particular, rifampin is a typical antimycobacterial drug.

The reason why it can kill mycobacteria is due to its lovely pharmacodynamics: it stops bacterial RNA synthesis by binding to the beta subunit of bacterial RNA polymerase. Human polymerase has no affinity for this molecule, so the drug is selectively bactericidal.

Pharmacokinetic is fantastic too. Orally administered, rifampin is well absorbed, reaches almost every centimeter of your body, where those vicious mycobacteria may be. Only the cerebrospinal fluids are hard to be reached, unless there's some meningeal inflammation going on.

Well, theoretically, it seems all nice and smooth, but, unfortunately, you always have to bear in mind resistance: rpoB is the gene which codes for the said beta subunit, and there is a wide spectrum of point mutations a bacterium can choose from to protect itself. And mycobacteria are a class of their own, when it comes to develop resistance. Not to mention their ability to become dormant in order to protect themselves.

Basically, we use rifampin when we get tuberculosis, often with another drug capable of killing mycobacterium tuberculosis because no cross-resistance has been noticed to date.
Mr. I-don't-like-to-grow-in-vitro M. leprea can be attacked using dapsone AND rifampin.

This drug is commonly used prophylactically in children who might develop Haemophilus influenzae type b disease.
However, my favourite regimen remains a triple therapy of rifampin, ceftriaxone and, ready for this, vancomycin to tackle meningitis caused by worryingly increasing penicillin-resistant pneumococci.

Sadly, there are many side effects.
Urine, sweat, tears and even contact lenses get orange (very popular in the Netherlands, I guess).
Light chain proteinuria is usually reported.

A flu-like syndrome can also occur: fever, myalgias, anemia, thrombocytopenia and tubular necrosis being the features of this phenomenon.

Although they are reported, jaundice and hepatitis are rare of consequences of the use of rifampin.

Interestingly, this drug is a potent inducer of citochrome P450 enzymes. This means that methadone, anticoagulants and contraceptives are inactivated, as well as drugs such as ketoconazole, chloramphenicol and theophylline.